Optimal Procedures of Allogeneic Transplantation for BCR::ABL1-Negative Atypical Chronic Myeloid Leukemia

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an only therapeutic option to provide a curative outcome for atypical chronic myeloid leukemia (aCML). Due to its rarity, the optimal transplant procedures have not been established. We herein conducted a nationwide retrospective study focusing on the prognostic impacts of transplant procedures, such as conditioning intensity and donor source, in aCML patients.

Methods

This study included aCML patients (i) who were 16 years or older, (ii) who received their first allo-HSCT between 2003 and 2021, and (iii) who were reported as negative for the presence of the t(9;22)(q34;q11) cytogenetic translocation and for the BCR::ABL1 transcript. The clinical data of 74 patients were collected from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. To identify variables potentially affecting outcomes, overall survival (OS), graft-versus-host disease (GVHD)- and relapse-free survival (GRFS), and chronic GVHD-free survival (CRFS) were examined using Cox proportional hazards regression models, and cumulative incidences of relapse (CIR), non-relapse mortality (NRM), neutrophil engraftment, and platelet recovery were investigated using the Fine and Gray proportional hazards model for the subdistribution of competing risks.

Results

In a total of 74 patients, median age at allo-HSCT was 54years (range, 18-72). Regarding transplant procedures, 54 (73.0%) and 20 (27.0%) patients received myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), respectively; and 11 (14.9%), 35 (47.3%), 19 (25.7%), and 9 (12.2%) patients used HLA-matched related donor (HMR), unrelated bone marrow/peripheral blood stem cell (UR-BM/PBSC), unrelated cord blood (U-CB), and HLA-haploidentical related (Haplo-R) donor, respectively. In allo-HSCT from Haplo-R donor, 6 out of 9 patients used post-transplant cyclophosphamide as GVHD prophylaxis. Over the four time periods (2003-2007, 2008-2012, 2013-2017, and 2018-2021), there was a progressive increase in the use of RIC regimen and U-CB/Haplo-R donor.

As for condition intensity, no significant difference was observed in the unadjusted probabilities of OS, CRFS, GRFS, CIR, NRM, and neutrophil engraftment incidence between MAC and RIC regimens, but the unadjusted incidence of platelet recovery tend to be low in RIC regimen than MAC regimen with a marginal significance (P=0.09). In the multivariate analysis, RIC regimen showed no significant difference in OS, CRFS, GRFS, CIR, NRM, and neutrophil engraftment compared to MAC regimen. RIC regimen showed a significant lower incidence of platelet recovery than MAC regimen (Hazard ratio (HR) [95% confidential interval], 0.40 [0.16-0.99]; P=0.048). In MAC and RIC regimens, the 3-year adjusted probability of OS was 50.1% and 74.7%; the 3-year adjusted CIR was 44.3% and 33.1%; and the 3-year adjusted NRM was 13.5% and 22.8%, respectively.

Regarding donor source, the unadjusted probabilities of OS, CRFS, GRFS, CIR, and NRM were not significant difference among four donor sources. The unadjusted incidence of hematopoietic recovery was significant lower in U-CB than HMR: neutrophil engraftment (P=0.008) and platelet recovery (P=0.002). In the multivariate analysis, the use of alternative donor (UR-BM/PBSC, U-CB, and Haplo-R donor) did not have any significant impact on OS, CRFS, GRFS, CIR, and NRM compared to HMR. U-CB significantly correlated with lower neutrophil engraftment (HR, 0.26 [0.10-0.64]; P=0.003) and platelet recovery (HR, 0.17 [0.07-0.44]; P<0.001) than HMR. In HMR, UR-BM/PBSC, U-CB, and Haplo-R donor, the 3-year adjusted probability of OS was 76.7%, 68.3%, 37.5%, and 60.8%; the 3-year adjusted CIR was 41.9%, 42.0%, 37.9%, and 38.5%; and the 3-year adjusted NRM was 12.0%, 26.2%, 27.4%, and 0.0%, respectively.

Conclusion

This study demonstrated that RIC regimen can provide the long-term remission in aCML patients as well as MAC regimen. Another significant point is that no significant difference of the post-transplant outcomes was observed in donor sources. Although careful management for hematopoietic recovery is necessary in allo-HSCT using RIC regimen and U-CB, the use of RIC regimen and alternative donor would be a feasible strategy to achieve curative outcomes in aCML patients.

Miyazaki:Kyowa-Kirin: Honoraria; Sumitomo Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria; Eizai: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria; Janssen Pharmaceutical: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria; Chugai: Honoraria. Kondo:Pfizer Inc.: Honoraria; Astellas Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria. Uchida:Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Daiichi Sankyo Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Kyowa Kirin Co.: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; AbbVie GK: Honoraria; AstraZeneca: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; JCR Pharmaceuticals Co.: Research Funding; Nippon Boehringer Ingelheim Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Fuji Pharma Co.: Research Funding; CSL Behring: Honoraria; Chugai Pharmaceutical Co.: Research Funding; MSD (Merck & Co. Inc.): Honoraria; Takeda Pharmaceutical Co.: Consultancy; Astellas Pharma Inc.: Honoraria; Astellas Pharma Inc.: Consultancy; Novartis Pharma Co.: Honoraria. Kanda:Sanofi K.K.: Honoraria; asclepia: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; ASAHI KASEI PHARMA CORPORATION: Honoraria; NIPPON KAYAKU CO．，LTD．: Honoraria; Ono Pharma Inc.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Eisai: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; AbbVie Inc.: Consultancy, Honoraria; Megakaryon Co: Consultancy; Amgen Pharma Inc.: Honoraria; SymBio Pharmaceuticals, Ltd.: Consultancy; DAIICHI SANKYO Co., Ltd.: Consultancy, Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Novartis Pharma K.K.: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Janssen Pharmaceutical K.K.: Consultancy, Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; MSD K.K.: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; CSL Behring K.K.: Honoraria. Atsuta:Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Meiji Seika Pharma Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Consultancy.